Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation
Christopher J. Hall, … , Nicola Dalbeth, Philip S. Crosier
Christopher J. Hall, … , Nicola Dalbeth, Philip S. Crosier
Published March 26, 2018
Citation Information: J Clin Invest. 2018;128(5):1752-1771. https://doi.org/10.1172/JCI94584.
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Research Article Immunology Inflammation

Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation

Abstract

Gout is the most common inflammatory arthritis affecting men. Acute gouty inflammation is triggered by monosodium urate (MSU) crystal deposition in and around joints that activates macrophages into a proinflammatory state, resulting in neutrophil recruitment. A complete understanding of how MSU crystals activate macrophages in vivo has been difficult because of limitations of live imaging this process in traditional animal models. By live imaging the macrophage and neutrophil response to MSU crystals within an intact host (larval zebrafish), we reveal that macrophage activation requires mitochondrial ROS (mROS) generated through fatty acid oxidation. This mitochondrial source of ROS contributes to NF-κB–driven production of IL-1β and TNF-α, which promote neutrophil recruitment. We demonstrate the therapeutic utility of this discovery by showing that this mechanism is conserved in human macrophages and, via pharmacologic blockade, that it contributes to neutrophil recruitment in a mouse model of acute gouty inflammation. To our knowledge, this study is the first to uncover an immunometabolic mechanism of macrophage activation that operates during acute gouty inflammation. Targeting this pathway holds promise in the management of gout and, potentially, other macrophage-driven diseases.

Authors

Christopher J. Hall, Leslie E. Sanderson, Lisa M. Lawrence, Bregina Pool, Maarten van der Kroef, Elina Ashimbayeva, Denver Britto, Jacquie L. Harper, Graham J. Lieschke, Jonathan W. Astin, Kathryn E. Crosier, Nicola Dalbeth, Philip S. Crosier

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Figure 10

Exogenous H2O2 can rescue MSU crystal–driven il1b expression following endogenous mROS depletion.

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Exogenous H2O2 can rescue MSU crystal–driven il1b expression following e...
(A) Schematic of H2O2 rescue strategy (following STAT3 IP–, MitoTEMPO-, AG490-, and etomoxir-mediated endogenous mROS depletion) and constructs for live imaging of macrophage H2O2 levels. (B) Ratiometric HyPer imaging (488/405 nm ratio is displayed as a heatmap, with warmer colors representing higher H2O2 levels) of H2O2 in single hindbrain macrophages from mpeg1:Gal4FF/UAS:HyPer-injected larvae before and after injection of PBS or 50 μM H2O2. (C) Quantification of HyPer ratios as detected in B, measured as normalized maximum 488/405 nm ratios within individual macrophages (n = 4 larvae/treatment). (D) Expression of il1b in MSU crystal–injected larvae treated with DMSO, STAT3 IP (125 μM), MitoTEMPO (250 μM) (with and without coinjection of 50 μM H2O2), or dnikbaa (DN) with MitoTEMPO (250 μM) plus H2O2 (50 μM). Arrows mark il1b expression in hindbrain. The numbers in parentheses represent the frequency of larvae with the indicated phenotype. (E) Quantification of il1b expression, as detected in D. Data were pooled from 2 independent experiments and represent the mean ± SD. ****P < 0.0001, by Student’s t test. Scale bars: 10 μm (B) and 100 μm (D).